Taylor & Francis Group

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FGF21 and autophagy coordinately counteract kidney disease progression during aging and obesity

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journal contribution
posted on 2023-09-19, 01:01 authored by Satoshi Minami, Shinsuke Sakai, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Atsushi Takahashi, Jun Matsuda, Hiroaki Yonishi, Jun Nakamura, Shihomi Maeda, Sho Matsui, Isao Matsui, Yoshitaka Isaka

Chronic kidney disease (CKD) has reached epidemic proportions worldwide, partly due to the increasing population of elderly and obesity. Macroautophagy/autophagy counteracts CKD progression, whereas autophagy is stagnated owing to lysosomal overburden during aging and obesity, which promotes CKD progression. Therefore, for preventing CKD progression during aging and obesity, it is important to elucidate the compensation mechanisms of autophagy stagnation. We recently showed that FGF21 (fibroblast growth factor 21), which is a prolongevity and metabolic hormone, is induced by autophagy deficiency in kidney proximal tubular epithelial cells (PTECs); however, its pathophysiological role remains uncertain. Here, we investigated the interplay between FGF21 and autophagy and the direct contribution of endogenous FGF21 in the kidney during aging and obesity using PTEC-specific fgf21- and/or atg5-deficient mice at 24 months (aged) or under high-fat diet (obese) conditions. PTEC-specific FGF21 deficiency in young mice increased autophagic flux due to increased demand of autophagy, whereas fgf21-deficient aged or obese mice exacerbated autophagy stagnation due to severer lysosomal overburden caused by aberrant autophagy. FGF21 was robustly induced by autophagy deficiency, and aged or obese PTEC-specific fgf21- and atg5-double deficient mice deteriorated renal histology compared with atg5-deficient mice. Mitochondrial function was severely disturbed concomitant with exacerbated oxidative stress and downregulated TFAM (transcription factor A, mitochondrial) in double-deficient mice. These results indicate that FGF21 is robustly induced by autophagy disturbance and protects against CKD progression during aging and obesity by alleviating autophagy stagnation and maintaining mitochondrial homeostasis, which will pave the way to a novel treatment for CKD.


This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan (17K16082 [to S.Minami], 19K17741 [to S.S.],17K16083 and 21K16163 [to T.Y.], 15K09260 and 18K08208 [to Y.T.], and 17H04188 [to Y.I.]), Japan Agency for Medical Research and Development (AMED) (JP22gm1410014 [to Y.I., S.Minami, and T.Y.]), the Project MEET, Osaka University Graduate School of Medicine (to S.Minami), the Mitsubishi Tanabe Pharma Corporation (to S.Minami), and Bayer Academic Support (to T.Y.).